Emerging Roles of Ubiquitin-Specific Protease 25 in Diseases

Abstract

The balance of ubiquitination and deubiquitination plays diverse roles in regulating protein stability and cellular homeostasis. Deubiquitinating enzymes catalyze the hydrolysis and removal of ubiquitin chains from target proteins and play critical roles in various disease processes, including cancer, immune responses to viral infections and neurodegeneration. This article aims to summarize roles of the deubiquitinating enzyme ubiquitin-specific protease 25 (USP25) in disease onset and progression. Previous studies have focused on the role of USP25 in antiviral immunity and neurodegenerative diseases. Recently, however, as the structural similarities and differences between USP25 and its homolog USP28 have become clear, mechanisms of action of USP25 in cancer and other diseases have been gradually revealed.

USP25 Deficiency Exacerbates Acute Pancreatitis via Up-Regulating TBK1–NF-κB Signaling in Macrophages

“…These findings are in line with previous studies showing that overexpression of USP25 reduces LPS-induced macrophage activation and inflammatory cytokines production. 20 Moreover, Usp25 knockdown has been shown to generate proinflammatory effects in Kupffer cells. 48 Taken together, these studies indicate that increasing Usp25 activity may counter inflammatory responses in AP.…”

“… 19 Specifically, expression of USP25 decreases lipopolysaccharide-induced inflammatory cytokine production in macrophages, and negatively regulates virus-induced type I interferon signaling in Human embryonic kidney (HEK)-293T cells. 20 , 21 , 22 Based on this important role of USP25 in the suppression of inflammatory responses, we explored whether USP25 is involved in AP pathogenesis.…”

ALDH1A3 Segregated Expression and Nucleus-Associated Proteasomal Degradation Are Common Traits of Glioblastoma Stem Cells

“…Indeed, a number of intronic mutations, leading to the ALDH1A3 aberrant splicing [35,36] as well as ALDH1A3 fusion transcripts (http://atlasgeneticsoncology.org/ Genes/GC_ALDH1A3.html accessed on 17 December 2021), have been identified. Interestingly, one of the known fusion partners of ALDH1A3 is USP25, a ubiquitin-dependent protease, which localizes in both nucleus and cytoplasm and has been implicated as a tumor-promoting factor in different types of human cancers [37]. In order to unequivocally identify the precursor protein for truncated ALDH1A3 peptides the determination of their amino acid composition should be the next step.…”

USP28: Oncogene or Tumor Suppressor? A Unifying Paradigm for Squamous Cell Carcinoma

“…All USP28 inhibitors developed to date also target USP25. As recent reports described USP25 as an oncoprotein in diverse tumor entities [127,129], the co-inhibition of USP25 by the current available USP25/USP28 dual specific inhibitors for cancer therapy might, therefore, not be an issue. Nevertheless, the oncogenic function of USP25 in SCC remains unexplored and more studies are required to prove the safety of the double inhibition in this tumor entity.…”